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COVID-19 Susceptibility, Severity Loci Reported by International Team

NEW YORK – More than a dozen parts of the genome show ties to SARS-CoV-2 infection susceptibility or severity, according to the latest research from an international team led by investigators at the University of Helsinki's Institute for Molecular Medicine Finland (FIMM), the Broad Institute, and Massachusetts General Hospital.

In a paper published Thursday in Nature, co-corresponding authors Benjamin Neale, co-director of the Broad's medical and population genetics program, FIMM Director Mark Daly, FIMM group leader Andrea Ganna, and their colleagues noted that "this working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed, for any complex human disease."

Members of the COVID-19 Host Genetics Initiative brought together genetic and clinical data for as many as 49,562 individuals of European, African, Middle Eastern, South Asian, East Asian, or admixed American ancestry who were treated for COVID-19 infections in 19 countries, searching for variants that were overrepresented in these individuals compared to roughly 2 million SARS-CoV-2-free control individuals from the same populations, including research-consented 23andMe customers.

With a handful of genome-wide association study meta-analyses, the team highlighted 13 loci with significant links to SARS-CoV-2 infection, including distinct loci linked to infection susceptibility or to COVID-19 severity. For example, the sites linked to infection in general included the chromosome 9 ABO blood locus, as well as a locus in the chromosome 3p21.31 region, near a locus implicated in disease severity in the past.

Loci with genome-wide significant ties to COVID-19 tended to turn up in genes or pathways previously implicated in lung cancer or lung functions, autoimmune conditions, or inflammatory disease-related processes, the team reported, and provided clues to potential treatment targets.

"The better we get at treating COVID-19, the better equipped the medical community could be to manage the disease," Neale said in a statement, adding that "a mechanism of treating infection and getting someone out of the hospital … would radically alter our public health response."

With the help of Mendelian randomization, meanwhile, the investigators saw causal associations between particularly severe COVID-19 cases and factors such as smoking or body mass index. On the other hand, past type 2 diabetes diagnoses did not appear to bump up infected individuals' risk of severe disease, contrary to prior suggestions.

In a related "News and Views" article in Nature, Brigham and Women's Hospital genetics researcher Samira Asgari and science writer Lionel Pousaz called the study "important not only for advancing our understanding of human susceptibility to COVID-19" but also for underscoring the importance of global collaborations for understanding infectious disease susceptibility.

Even so, they cautioned that "despite the authors' efforts to include genetically diverse study groups, about 80 percent of the participants are of European ancestry" and argued that "studies containing a larger number of individuals from other ancestry groups are needed to ensure that the results apply to non-Europeans, and to identify other loci that might be associated with risk in people of other ancestries."

For his part, Daly called the team "much more successful than past efforts in sampling genetic diversity," through efforts to reach global populations, though he said there is "a long way to go."

In the international dataset considered so far, for example, the COVID-19 Host Genetics Initiative team flagged a COVID-19 severity-associated locus near the lung cancer-related gene FOXP4 that appeared to be found at higher frequencies in individuals from East Asian, admixed American, and Middle Eastern populations compared to individuals of European descent.

The investigators are digging into the available data and continuing to collect additional genetic and clinical clues, to better distinguish between susceptibility and severity effects for specific loci, while searching for potential contributors to long-term symptoms in so-called COVID-19 "long-haulers" in an effort to better understand, manage, and treat SARS-CoV-2 infections down the road.

"Future work will be required to better understand the biological and clinical value of these findings," the authors wrote. "Continued efforts to collect more samples and detailed phenotypic data should be endorsed globally, allowing for more thorough investigation of variable, heritable symptoms, particularly in the light of the newly emerging strains of SARS-CoV-2 virus, which may provoke different host responses leading to disease."

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